Engineering of acetaminophen particle attributes using a wet milling crystallisation platform.

Wet milling coupled with crystallisation has considerable potential to deliver enhanced control over particle attributes. The effect of process conditions and wet mill configuration on particle size, shape and surface energy has been investigated on acetaminophen using a seeded cooling crystallisation coupled with a wet mill unit generating size controlled acetaminophen crystals through an interchangeable rotor-tooth configuration. The integrated wet milling crystallisation platform incorporates inline focused beam reflectance measurement (FBRM) and particle vision measurement (PVM) for in-depth understanding of particle behaviour under high-shear conditions. We used a recently developed computational tool for converting chord length distribution (CLD) from FBRM to particle size distribution (PSD) to obtain quantitative insight into the effect of the competing mechanisms of size reduction and growth in a wet milling seeded crystallisation process for acetaminophen. The novelty of our wet milling crystallisation approach is in delivery of consistent surface energies across a range of particle sizes. This highlights the potential to engineer desirable particle attributes through a carefully designed, highly intensified crystallisation process.